Tinnitus, the perception of a sound without an external acoustic source, can be suppressed briefly following the offset of an external sound. This phenomenon, termed residual inhibition, has been known for almost four decades, although its underlying cellular mechanism remains unknown. The goal of the proposed research is to elucidate the mechanism(s) responsible for residual inhibition to identify a class of drug that can either prolong residual inhibition or suppress tinnitus without the application of any external sounds. Preliminary observations in our laboratory have established the foundation for a theoretical and methodological approach to study residual inhibition. We have found that a loud, long-lasting sound stimulus (typical for sounds that evoke residual inhibition) can suppress spontaneous firing in central auditory neurons for as long as the duration of residual inhibition. Abnormally high spontaneous firing has been linked to behavioral manifestations of tinnitus; therefore, suppression of this firing is a plausible candidate for the underlying mechanism of residual inhibition. Three major hypotheses will be tested in the proposed project. First, we hypothesize that sound stimuli lasting several seconds, which typically trigger seconds of residual inhibition, suppress spontaneous firing in auditory neurons for as long as the residual inhibition lasts. We will measure the duration of suppression of spontaneous firing in auditory neurons in mice with tinnitus in response to sound stimuli of several seconds. Second, we hypothesize that metabotropic glutamate receptors (mGluRs) play a key role in this suppression. We will quantify the suppression in auditory neurons recorded extracellularly before and after iontophoretic application of drugs targeting mGluRs. Third, we hypothesize that there is a link between sound-triggered suppression in auditory neurons and residual inhibition. To test this hypothesis, we will inject the mGluR-targeting drugs that affect suppression systemically to determine whether these drugs also affect residual inhibition. Drugs targeting mGluRs are suitable for treating tinnitus because they bind to mGluRs at nanomolar concentrations, easily penetrate the blood-brain barrier and yet show few clinical side effects. PUBLIC HEALTH RELEVANCE: The proposed study will improve our knowledge of the central mechanisms responsible for tinnitus and provide a foundation for the development of therapeutic drugs to treat tinnitus.